AUTHOR=Warner Sophie C. , Nair Anjali , Marpadga Rahul , Chubinskaya Susan , Doherty Michael , Valdes Ana M. , Scanzello Carla R. 

TITLE=IL-15 and IL15RA in Osteoarthritis: Association With Symptoms and Protease Production, but Not Structural Severity

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01385

DOI=10.3389/fimmu.2020.01385

ISSN=1664-3224

ABSTRACT=<p><bold>Objective:</bold> Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is increased in joint fluids of early-stage osteoarthritis (OA) patients, and has been associated with expression of proteases that can damage cartilage, and the development of neuropathic pain-like symptoms (NP) after nerve injury. The objective of this study was to further explore the role of IL-15 in the pathogenesis of OA cartilage degeneration and test genetic variation in the IL-15 receptor α gene (<italic>IL15RA</italic>) for an association with OA with radiographic severity and symptoms.</p><p><bold>Methods:</bold> Cartilage samples from donors (<italic>n</italic> = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 <italic>in vitro</italic> using explant cultures. Data from two independent Nottinghamshire-based studies (<italic>n</italic> = 795 and <italic>n</italic> = 613) were used to test genetic variants in the <italic>IL15RA</italic> gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP.</p><p><bold>Results:</bold> IL-15Rα was expressed in chondrocytes from cartilage obtained from normal and degenerative knees. IL-15 significantly increased the release of matrix metalloproteinase-1 and -3 (MMP-1 and -3), but did not affect loss of proteoglycan from the articular matrix. Genetic variants in the <italic>IL15RA</italic> gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10–1.98 <italic>p</italic> &lt; 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63–0.92 <italic>p</italic> &lt; 0.01) but not with radiographic severity.</p><p><bold>Conclusions:</bold> In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although <italic>ex vivo</italic> cartilage explants could respond to IL-15 with increased protease production, we found no effect of IL-15 on cartilage matrix loss and no association between <italic>IL15RA</italic> variants and radiographic severity. Together, these results suggest that IL-15 signaling may be a target for pain, but may not impact structural progression, in OA.</p>